The search for compounds showing anti-tumor activity has, in recent years, included fused ring structures such as derivatives of anthracene, and heterocyclics such as isoquinoline and acridine. The first anthracene derivative to show promise was 2,2'-(9,10 anthracene-dimethylene)bis-(2-thiopseudourea)dihydrochloride, which unfortunately suffered from phototoxicity (U.S. Pat. No. 3,190,795 and Carter, Cancer Chemother. Rep., 1, 153-163, 1968). See also, Frei, E. III, et al., Cancer Chemother Rep., 55, 91-97 (1971). Furthermore, Brana, et al. in Cancer Chemother Pharmacol, 4, 61-66 (1980) and in Eur. J. Med., 16, 207-212 (1981) disclose 2- and 5- substituted benz[de]-isoquinoline-1,3-diones having the formula: ##STR2## wherein X is H, NO.sub.2, NH.sub.2, Cl, OH, NHCO.sub.2 Et, OCH.sub.3, NHCOCH.sub.3 or t-Bu and Y is a disubstituted amine, OH, OCH.sub.3, CH(CH.sub.3).sub.2, SH or NHCOCH.sub.3 and n is an integer ranging from zero to three. It is alleged that the compounds therein inhibit HeLa Cells.
Miller, et al. in U.S. Pat. No. 4,108,896 discloses compounds having the formula: ##STR3## wherein A is a straight or branched alkylene chain having from 1 to 6 carbon atoms; R.sub.1 and R.sub.2 are each selected from the group consisting of hydrogen, lower alkyl having from 1 to 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl having from 3 to 6 carbon atoms in which the unsaturation is in a position other than in the 1-position of the alkenyl group, or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached, represent the pyrrolidinyl, piperidino or morpholino radical; R.sub.3 is selected from the group consisting of hydrogen and the radical, ##STR4## with the proviso that one and only one such R group is hydrogen.
The compounds are disclosed as having use as antiviral agents.
However, the teachings of the references discussed hereinabove are limited to the anthracene and isoquinoline derivatives. None of these references suggest that the dibenzisoquinoline 1,3-diones of the present invention would be useful and effective as anti-tumor agents.
Amonafide (NSC 308847) is an isoquinoline dione derivative having anti-tumor activity. More specifically, amonafide, amino-N-dimethylaminoethylbenz[de]-isoquinoline, has undergone extensive tests for its anti-tumor activity. The National Cancer Institute prepared and distributed a brochure summarizing the anti-tumor activity of amonafide in 1984. Although the level of activity found for amonafide was and continues to be of high interest, this material does have significant deficiencies which indicate the continuing need for agents with improved properties. In the first place, amonafide has produced substantial myelotoxicity leading to some deaths in patients receiving five daily doses of the drug. In addition, this report showed that amonafide had only moderate activity in leukemia models in mice. Also, it showed that amonafide has no activity in human tumor xenografts in mice with colon, lung and mammary cancers. Thus, while amonafide showed significant activity, it does not have a substantially broad spectrum of activity in murine tumor models.
Another group has shown that amonafide or natidimide as poor activity when tested in primary human solid tumors in vitro. See, Ajani, J. A. et al., Invest New Drugs, 6, 79-83 (1988).
In view of the shortcomings of these various drugs available heretofore, the present inventors searched for other drugs which were more effective anti-cancer agents. They searched for compounds having the following characteristics:
1) Increased tumor cell cytotoxtc potency;
2) Minimal, if any, cross resistance with multidrug resistant (MDR) tumor cells;
3) Relativity low cytotoxic potency in normal heart cells;
4) Activity in malignant tumors, especially solid tumors, hematological tumors, and leukemia.
As a result of their research, the present inventors have developed compounds meeting these objectives. The present inventors have found that compounds based on anthracene instead of naphthalene show surprising anti-tumor activity.